Design challenges facing clinical trials of the effectiveness of new HIV prevention technologies.

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Abstract

Recent successes of antiretroviral pre-exposure prophylaxis (PrEP) in preventing HIV infection
have raised questions whether further placebo controlled trials of new HIV-prevention
technologies are ethically justifiable. A trial with active agent(s) in the comparator group can be
designed either as a superiority or non-inferiority trial. In a non-inferiority trial the hypothesis
tested is that the intervention is not inferior to, by a predefined clinically relevant amount, or at
least as effective as, the comparator. Non-inferiority trials pose challenges in data interpretation.
Firstly it is possible to show equivalence of two non-effective interventions. If the active
comparator intervention is ineffective, the new intervention would be shown to be non-inferior to
this inactive intervention, while neither intervention is superior to placebo or no intervention. The
second challenge is that any effect that dilutes the true efficacy of an intervention in a trial, such as
non-adherence, loss to follow-up or protocol violations, makes it easier for the two interventions
to be declared equivalent. Non-differential low adherence is unlikely to lead to the conclusion that
an inferior intervention is non-inferior. However, differential adherence between study arms,
which is more likely in non-blinded trials, is likely to bias the results and lead to incorrect
conclusions.
Investigators conducting non-inferiority trials will have to pay special attention to supporting,
measuring and maintaining high adherence. The goal in future non-inferiority trials should be to
maintain similar levels of high adherence in all study arms, but at a minimum to reduce the
likelihood of differential adherence across study arms.